Estrogens exert neuroprotective influences in several models of brain damage. To date, however, little basic research has addressed the relationship between these protective effects and preservation of brain function. This R15 application proposes research to test the hypothesis that estrogen treatment protects against the neuronal loss and cognitive deficits that typically result from transient global ischemia. These studies also explore the mechanisms through which estrogens exert protective effects through the use of targeted administration of estrogens and estrogen receptor antagonists. Specific Aim 1 investigates whether performance on learning and memory tasks is preserved by pre-ischemic administration of estradiol, the extent to which this effect is related to neuroprotection in the hippocampus, and the relationship between time-course and dose of hormone exposure. These studies involve manipulation of hormone levels prior to transient global ischemia or sham surgical procedures. Spontaneous alternation is assessed on the Y-maze and spatial learning is assessed with a water maze task. Following behavioral testing, hippocampal neuronal loss is assessed and compared with performance on the behavioral tasks. These studies are important because they address the critical connection between structure (neuroprotection) and function (preservation of behavior). They also address fundamental questions; related to dose and timing of hormone administration that are of significant clinical interest. Specific Aim 2 investigates whether the protective effects of estradiol are due to its actions at intracellular estrogen receptors in the hippocampus by administering estradiol and an estrogen receptor antagonist (ICI 182,780) directly to the hippocampus. These studies have clinical relevance as they address the extent to which estradiol-mediated neuroprotection is related to preservation of behavioral function and the extent to which estradiol's effects are due to actions in the hippocampus.